Spranger Lab aims to elucidate immune response to cancer

Cancer is a wily disease. Tumors are constantly mutating and developing new ways to evade drugs and our bodies’ natural defenses. Because cancer cells are constantly changing, the pathology is difficult to target and cure en masse. Immunotherapy research is a burgeoning field that aims to help our own immune systems clear the disease in a personalized manner, and for some individuals, the method shows much promise. However, for others, this approach is ineffective. The Spranger Lab hopes to understand these varying responses to immunotherapy.

“It’s very important that we understand what differentiates a person who responds to [immunotherapy] versus someone who doesn’t,” says graduate student Kim Nguyen, who works in the Spranger lab. “The clinical data is very ahead of the basic science. Now we’re just kind of catching up to the clinical data to understand what is happening biologically, mechanistically, and to me that’s really important. I don’t think we should be happy with just injecting drugs into people and being like, ‘yes, it works.’”

There is already knowledge surrounding immune responses to cancer. Cells normally break down some of their own proteins and present them on their surfaces. T cells, important players in the immune response, recognize these digested proteins, or antigens, as signals of normal functioning. When foreign bacterial or viral proteins are broken down and presented instead, T cells are warned that the body’s health is compromised. T cells and various other members of the immune system such as dendritic cells, which help kick off the immune response by digesting antigen materials and presenting them to T cells, can then clear the body of such threats.

Cancer develops when our own cells mutate and go off the rails. One might think that normally functioning immune systems would not be able see our own cells as problematic, but studies have demonstrated that T cells can recognize these mutated “self” cells as a threat to be combatted. This is because cancer cells might make more of a certain protein than normal, such that the proteins they present would not be expressed on a normal cell. These are called tumor-associated antigens. Alternatively, cancer cells might produce mutated proteins. When these proteins broken down and presented on the surface, they are called neoantigens. Immunotherapy uses various methods to stimulate and strengthen this response.

The Spranger lab builds off of this knowledge with a two-pronged approach. One area of their research involves digging more deeply into the ways different immune cell populations, and in particular, dendritic cells, interact with cancers. Some cancer models have demonstrated an ability to “hamper the immune response by altering a particular subset of dendritic cells so that they would no longer be able to help traffic T cells into a tumor,” Nguyen explains.

The other area of research involves “identifying pathways that different cancers may be utilizing to suppress the immune system or evade it, with particular interest in how they might be modulating the T cell response,” Nguyen says. Nguyen’s main work deals with this altered modulation in cancer, and she is specifically focusing on pancreatic cancer. In using different mouse models designed for studying particular pathways, Nguyen hopes to distinguish between mice with tumors that are infiltrated by T cells and mice with tumors that are not invaded by T cells. In doing so, she and the lab hope to explore and understand these differences in immune response.

In the long run, findings from this research could contribute to the development of immunotherapies that are effective in more cancer patients, as well as to a greater understanding of the mechanisms behind such treatments. In the present, Nguyen and other lab members are in the beginning stages, working to develop and grow their mouse models. “There’s a possibility that the candidates we’re chasing might not actually be bona fide pathways that these cancer cells are using to evade or suppress the immune system. This is not low-hanging fruit, so it’s a riskier project,” Nguyen said, expressing worries that are ever present in this line of research, “but I’m optimistic.”

As part of another project in line with the lab’s mission, Nguyen is in collaboration with members of Michael Birnbaum’s lab in MIT’s bioengineering department. “We want to characterize neoantigens as far as the strength of the T cell response they can elicit,” she said. “Let’s say you have one neoantigen that can elicit a very strong immune response[...] Is the response elicited by that one neoantigen able to effectively clear out an entire tumor, regardless of the type of neoantigen those tumor cells might be expressing?”

She sees this research being applied in the clinic in the future, particularly with respect to antigen vaccines, where protein fragments are injected into patients to stimulate certain T cell responses. “This [research] could help build our understanding of what kind of peptides would be most effective.” Such vaccines would ideally be personalized to the patient’s particular cancer.

Speaking about the future of cancer therapies, Nguyen says,“I think previously there was this idea that we could cure cancer, maybe with the thought that there must be something that unifies all cancers, but I think we are effectively moving away from that idea. I think the future is still personalized medicine, and what we’re doing now is essentially trying to understand as much about the cancer as we can, but also about how cancer is communicating with our own bodies, with the immune system, and hopefully in the future with personalized medicine, we can tackle different branches of whatever that might be.”